Ketamine and Major Depressive Disorder

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The number of individuals diagnosed with major depressive disorder (MDD) in the US has increased between 2005 and 2018 from 13.7 million to 17.5 million, with the prevalence rate rising from 6.8 to 7.1% . The rising prevalence is unevenly distributed by age, with the greatest increase seen among 18- to 34-year-olds.

Starting in early 2020, the pandemic resulted in new, stressful, and at times overwhelming worries about the health effects of the virus itself, heightened concerns about potential loss of employment, and prolonged social isolation involving greatly reduced interaction with family and friends. Recent data from the Centers for Disease Control and Prevention (CDC) show that the US prevalence of MDD has increased substantially from 7% prior to the pandemic to 27% during the first year of the pandemic, and MDD with anxiety disorders has increased from 11 to 38%.

While all mental illness can have serious negative implications on well-being, MDD is one of the most burdensome illness globally causing symptoms of feelings of deep loneliness, suicidal thoughts, and a general lack of enjoyment towards life.

“Since the disease varies extensively from person to person, it has been difficult to find a generally effective treatment plan. Additionally, individuals with MDD can be resistant to treatments.”

While the complexity and heterogeneity of MDD has made it challenging for mental health professionals to find effective treatment strategies, there are several therapies that work for a large number of patients, including Cognitive Behavioral Therapy and medications such as Selective Serotonin Reuptake Inhibitors (SSRIs). CBT was found to have a 43% success rate in patients with depression. In a study with 100 participants, around 40-60% saw a reduction in their depression symptoms on SSRIs. In a study with 100 people, around 40-60 of the participants saw a reduction in their depression symptoms upon taking medication for treatment. While these first line approaches work well in some patients, others may require more advanced treatments such as Electroconvulsive Therapy (ECT) to obtain symptom relief. ECT has been shown to be the most effective treatment so far for MDD, yet it is typically resorted to last after previous approaches have been proven to be ineffective for the patient. It is only used as a last resort approach due to its high rate of side effects, including memory impairments which may continue to persist long after completing ECT.

There has been a recent increase in the study of psychedelic compounds in the treatment of several psychiatric disorders, in particular MDD and PTSD. John Hopkins School of Medicine investigators have reported evidence from multiple carefully controlled studies suggesting that psychedelics are effective in the treatment of mental disorders. A brain imaging study performed by scientists at UC San Francisco and Imperial College London analyzed fMRI brain scans from nearly 60 people who had participated in two psilocybin trials. The first one was an unblinded study in which all the participants had treatment-resistant depression and knew they were being given psilocybin. The second study was a randomized, placebo-controlled trial in which the participants had milder depression symptoms and were not told whether they had been given psilocybin or escitalopram, an SSRI antidepressant. In addition to the drugs, all the participants received the same type of psychotherapy.

The scans, which were done before and after treatment, showed that psilocybin treatment reduced connections within several brain networks that are tightly connected in depression and increased connections to other regions of the brain that had not been well integrated.

Participants also improved clinically, being less emotionally avoidant and experiencing improvements in cognitive functioning. The improvement in their depressive symptoms correlated with the observed brain changes, and these improvement persisted until the study ended three weeks after the second psilocybin dose.

This new research has encouraged scientists to dive deeper into the efficacy of psychedelics, such as ketamine, in the treatment of mental health disorders. Ketamine is a drug primarily prescribed for short term general anesthesia in infants. However, when administrated in intravenous doses, lower than those required to induced anesthesia, the drug has the ability to induce a psychedelic experience where individuals may experience hallucinations. Subanesthetic doses of ketamine have been administrated to treat patients with mental health disorders over the past two decades, but this approach has only recently received a lot of attention.

“…researchers wanted to see how using infusions of ketamine would compare in the efficacy of treatment in patients diagnosed with treatment resistant MDD. Their results were revolutionary to the developments of potential future treatments for patients.”

While ECT is more commonly used by medical professionals due to their familiarity with the treatment, researchers wanted to see how intravenous ketamine administration compares with ECT in the treatment in patients with treatment resistant MDD. A recent study published in The New England Journal of Medicine (NEJM) compared the effectiveness between ketamine infusions and ECT in the treatment resistant MDD .

“Following their completion of treatments, they found that 41.2% of the ECT group had reported a response from the treatment and 55.4% of the ketamine group had a response from their sessions of treatment.”

The study participants were split into two groups. All of the participants were diagnosed with treatment resistant MDD and had been referred to seek out ECT as a last resort treatment. Researchers initially recruited a total of 403 patients who were then assigned in a 1:1 ratio to be treated with either infusions of ketamine or ECT, where 170 were in the ketamine group and 195 were in the ECT group after 38 of the recruited patients had withdrawn. Researchers used self-report measures to evaluate the response in patients after the two groups received their different treatments. The ECT group completed a total of nine sessions and the ketamine group completed a total of six sessions. Following their completion of treatments, they found that 41.2% of the ECT group had reported a positive response from the treatment compared to 55.4% of the ketamine group. The two groups reported a similar improvement in their quality of life. Side effects of memory loss were seen amongst the ECT group as well as adverse musculoskeletal effects. In the ketamine group, milder side effects such as disassociation were observed. Disassociation may result in feelings of daydreaming, causing an individual to feel detached from their current reality and result in difficulties around retaining short-term memories. Aside from possible disassociation, minimal side effects were reported in the ketamine group.

In summary, the results of the well-controlled study in patients with MDD found that infusions of ketamine were more effective than ECT and presented little to no side effects. Even though more studies like this are needed to confirm these findings, the NEJM study suggest that subanesthetic intravenous ketamine may be a good option for those with treatment resistant major depression.

Ketamine has only been a recent therapy approach used for treatment resistant MDD, and some psychiatrist still feel hesitant about the safety and efficacy of the drug. Some medical professionals have even been entirely resistant to using it and other psychedelic drugs for their patients diagnosed with mental disorders. Future research around the safety and efficacy of ketamine is still needed, but these studies are helping to revolutionize the treatment of common and disabling mental disorders. It is likely that the stigma surrounding the use of psychedelics to treat mental illness will disappear when the drug being used for treatment in patients is found to be both safe and effective in clinical trials.

By Amanda Johnson with Emeran Mayer, MD

Amanda Johnson Amanda is a recent graduate from the University of Southern California where she received her degree in Psychology. In addition to her university studies, she earned her Integrative Nutrition Health Coach certification from the Institute of Integrative Nutrition (IIN).

This article was reviewed and approved by Emeran Mayer, MD